losartan-potassium and Thrombocytopenia

Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States and is higher among patients with advanced age.. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For those with higher-risk MDS, hypomethylating agents such as azacitidine, decitabine, or decitabine/cedazuridine are first-line therapy. Hematopoietic cell transplantation is considered for higher-risk patients and represents the only potential cure.. MDS are diagnosed in approximately 4 per 100 000 people in the United States and are associated with a 5-year survival rate of approximately 37%. Treatments are tailored to the patient's disease characteristics and comorbidities and range from supportive care with or without erythropoiesis-stimulating agents for patients with low-risk MDS to hypomethylating agents, such as azacitidine or decitabine, for patients with higher-risk MDS. Hematopoietic cell transplantation is potentially curative and should be considered for patients with higher-risk MDS at the time of diagnosis.

Topics: Antineoplastic Agents; Azacitidine; Decitabine; Erythropoietin; Female; Hematinics; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neutropenia; Prognosis; Thrombocytopenia

Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need.

Topics: Algorithms; Anemia; Disease Management; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Primary Myelofibrosis; Protein Kinase Inhibitors; Risk Factors; Splenectomy; Thrombocytopenia; Transplantation, Homologous

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and peripheral blood refractory cytopenias. MDS is recognized to be associated with an increased risk of symptomatic anemia, infectious complications and bleeding diathesis, as well as a risk of progression to acute myeloid leukemia, particularly in patients with a high IPSS score. The advent of use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) has improved symptoms in MDS patients in addition to some data that suggest there might be an improvement in survival. G-CSF is an effective therapeutic option in MDS patients, and it should be considered for the management of refractory symptomatic cytopenias. G-CSF and EPO in combination can improve outcomes in appropriate MDS patients such as those with lower-risk MDS and refractory anemia with ring sideroblasts (RARS) . This article reviews use of growth factors for lower-risk MDS patients, and examines the data for G-CSF, EPO and thrombopietic growth factors (TPO) that are available or being developed as therapeutic modalities for this challenging disease.

Topics: Anemia; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutropenia; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin

Chronic hepatitis C is one of the leading causes for chronic liver disease globally. The past two decades have seen many advances in hepatitis C treatment. Despite these advances, side effects of treatment are common. Haematological complications of treatment can result in treatment cessation and suboptimal results. Recent data have suggested a role for epoetin/granulocyte colony stimulating factor (G-CSF) in optimizing sustained virological response (SVR).. To investigate the nature, frequency and management of haematological side effects in the treatment of chronic hepatitis C infection.. The terms hepatitis C, hepatitis C virus (HCV), treatment, side effects, interferon, peginterferon, ribavirin, anaemia, haemoglobin, neutropenia, thrombocytopenia, haematological, growth factor, erythropoietin and G-CSF were searched on MEDLINE for the period 1991-2009. References from selected articles were also included.. Haematological side effects such as anaemia, neutropenia and thrombocytopenia are frequent in anti-HCV treatment. The off-label use of haematological growth factors is common and effective.. Erythropoietic agents are effective in treating anaemia, preventing ribavirin dose reduction, improving patients' quality of life, but the effect on SVR is not fully elucidated. G-CSF is effective in raising absolute neutrophil count; however, neutropenic HCV-infected patients on combination treatment may not experience increased bacterial infections. Eltrombopag, a new oral thrombopoietin mimetic, may allow combination treatment in patients with thrombocytopenia.

Topics: Anemia; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia; Viral Load

Supportive care constitutes the basis of the management of patients with myelodysplastic syndromes (MDS). Appropriate treatment of cytopenia, as well as of other related complications, not only improves quality of life but also may positively affect the overall survival of patients. Anemia is the most common cytopenia in MDS, and the requirement for regular transfusions is a major clinical problem for patients with low-risk MDS. An important therapeutic goal in this patient group is to maintain acceptable hemoglobin levels without transfusions. Today, this goal can be achieved by treatment with erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF), or by more targeted treatment such as antithymocyte globulin or lenalidomide in around 50% of patients. For the remaining patients, and for those who lose their therapeutic response, chronic transfusion therapy, with or without the addition of chelating agents, is the only option and it is important that this treatment is scheduled to meet the needs of the individual patient. Severe thrombocytopenia has recently been reported to respond to thrombopoietic agents, such as AMG 531.

Topics: Anemia; Colony-Stimulating Factors; Erythrocyte Transfusion; Erythropoietin; Hematopoiesis; Humans; Myelodysplastic Syndromes; Neutropenia; Prognosis; Recombinant Proteins; Thrombocytopenia

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2(V617F), the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.

Topics: Aged; Alkylating Agents; Anemia; Antimetabolites, Antineoplastic; Blood Coagulation Disorders; Disease Progression; Drug Delivery Systems; Drugs, Investigational; Erythropoietin; Hematopoiesis, Extramedullary; Humans; Immunologic Factors; Janus Kinase 2; Leukemia, Myeloid, Acute; Middle Aged; Mutation, Missense; Palliative Care; Point Mutation; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction; Thrombocytopenia

The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.

Topics: Anemia; Anemia, Diamond-Blackfan; Anemia, Dyserythropoietic, Congenital; Erythropoietin; Fanconi Anemia; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Stem Cell Factor; Thrombocytopenia

Pegylated interferon and ribavirin combination therapy represent the standard-of-care treatment for chronic hepatitis C, that allows to cure more than half of the patients. However, the success of this bitherapy is in balance with numerous side effects, especially hematologic and psychiatric. This review is focused on complementary treatments (erythropoietin, G-CSF, vitamin E, glutathion, ursodeoxycholic acid and antidepressants) likely to bring a benefit in maintaining adequate interferon and ribavirin dosages and in improving quality of life. This analysis has been performed by using the Medline(R) data base and with data from laboratories which commercialized these molecules. Erythropoietin, G-CSF and antidepressants are the best tools to optimize the bitherapy in its dose and its duration while privileging the quality of life of HCV-infected patients.

Topics: Anemia; Antidepressive Agents; Antioxidants; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

In patients with liver disease, thrombocytopenia is a clinical feature that may represent an obstacle to invasive diagnostic or therapeutic procedures, chemotherapy, and anti-viral treatment. Stimulation of the bone marrow is the most promising therapeutic intervention for thrombocytopenia in patients with chronic liver disease. The description of thrombopoietin and its (de)regulation in patients with chronic liver disease have disclosed new treatment opportunities. Indeed, pharmacologic treatment options for thrombocytopenia can be divided into treatments targeted at the thrombopoietin receptor (synthetic thrombopoietins and thrombopoietin-mimetic agents), and use of cytokines with general thrombopoietic potential. Unfortunately, use of synthetic thrombopoietin was hampered by the development of neutralizing antibodies, and thrombopoietin mimetic agents have not yet entered clinical studies. Interleukin-11 proved to be useful in increasing platelet count in patients with chronic liver disease, although its use is limited by side-effects. Erythropoietin has shown promising results in improving thrombocytopenia in cirrhotic patients. In patients with chronic liver disease, safe and well-tolerated treatments aimed at improving thrombocytopenia are still lacking. Larger studies are needed to evaluate and better characterize the thrombopoietic potential of erythropoietin. Human studies with thrombopoietin-mimetic agents are eagerly awaited in order to assess both effectiveness and safety of these drugs.

Topics: Chronic Disease; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Liver Diseases; Platelet Count; Receptors, Erythropoietin; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

Hematologic dysfunction, including thrombocytopenia, anemia, neutropenia, thromboses, and coagulopathy, occur commonly during critical illnesses. A major challenge is to identify drug-induced causes of hematologic dysfunction. Given the wide variety of drug-induced hematologic effects, clinicians always should consider any concomitant drugs in the differential diagnosis of acquired hematologic dysfunction. The most severe effects include drug-induced aplastic anemia, heparin-induced thrombocytopenia, and drug-induced thrombotic microangiopathy. Certain drugs are associated with multiple hematologic effects. For example, cisplatin can cause hemolytic uremia syndrome and erythropoietin deficiency, and quinine can precipitate immune-mediated thrombocytopenia, immune-mediated thrombocytopenia, and thrombotic microangiopathy.

Topics: Anemia, Aplastic; Anticoagulants; Erythropoietin; Hematologic Diseases; Heparin; Humans; Methyltransferases; Severity of Illness Index; Thrombocytopenia

Pegylated (PEG)-interferon and ribavirin combination therapy are the standard of care for the treatment of chronic hepatitis C and are associated with a high rate of sustained virologic response. However, there is a high incidence of hematologic side effects with this therapeutic regimen. Hematologic side effects are particularly common; bone marrow suppression caused by interferon may result in neutropenia and thrombocytopenia. Ribavirin is directly toxic to red blood cells and is associated with hemolysis, which is usually dose-related but self-limited. Historically, the traditional management of hematologic side effects of interferon therapy has been dose reduction. However, recent studies have shown that response to therapy is strongly influenced by adherence to optimal doses of interferon and particularly ribavirin. Therefore, there is increasing emphasis on the use of growth factors such as filgrastim and erythropoietin to stimulate bone marrow production of erythrocytes and leukocytes to allow patients to receive the optimal doses of interferon and ribavirin. The incidence, magnitude, and possible mechanisms of hematologic complications associated with interferon and ribavirin are described in this review.

Topics: Anemia, Hypochromic; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

Topics: Anemia, Hypochromic; Antiviral Agents; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Growth Substances; Hematinics; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Newborn infants in intensive care units, especially those born premature, are at particular risk for blood transfusion adverse effects. Aside improvements in the preparation of specific blood products for the neonatal period, such as multiple packed cells preparations from a single donor for multiple transfusions in premature infants, progress has involved prophylaxis of anemia of prematurity as well. Recombinant human erythropoietin has proven to be beneficial with high range evidence. Also, alternative methods have been proposed to compensate for the delay in the effect of rHuEPO, such as delayed clamping of umbilical cord at birth, or autologous placental blood transfusion. However, a better understanding of the indications of blood transfusion and the provision of practice guidelines may justify a re-evaluation of prophylactic strategies for anemia of prematurity.

Topics: Anemia; Antigens, Human Platelet; Blood Component Transfusion; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Exchange Transfusion, Whole Blood; Granulocytes; Humans; Immunity, Maternally-Acquired; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Intensive Care, Neonatal; Leukocyte Transfusion; Plasma; Platelet Transfusion; Practice Guidelines as Topic; Recombinant Proteins; Thrombocytopenia

Consensus guidelines are in place for treating chronic hepatitis C virus infection. This article highlights some of the hematologic complications of hepatitis C therapy. Management options are presented.

Topics: Anemia; Antiviral Agents; Bone Marrow; Epoetin Alfa; Erythropoietin; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon Type I; Neutropenia; Recombinant Proteins; Ribavirin; Thrombocytopenia

Myelodysplastic Syndrome (MDS) comprises a heterogeneous group of clonal hemopathies derived from an abnormality affecting a multipotent hematopoietic stem cell and characterized by maturation defects resulting in ineffective hematopoiesis. It most frequently occurs in elderly patients. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Most MDS patients, due to their age and co morbidity, are not eligible for allogeneic hematopoietic stem cell transplantation; the only established curative regimen. The effect of available lineage-specific growth factors is limited to improvement of single lineages and has not resulting in the survival benefit. Treatment with low dose Ara-C is disappointing in regard to response rate or duration. No benefit has been demonstrated in differentiation inducers such as retinoids and Vitamin D3 as single agents. We report a case of a patient with transfusion dependent MDS who was not a candidate for allogeneic stem cell transplantation or cytotoxic chemotherapy, who also failed to response to erythropoietin support but had a favorable response to 5-azacitidine. His blood transfusion requirement reduced significantly, and was correlated with the remarkable improvement of the pancytopenia, particularly anemia and thrombocytopenia after receiving the investigational therapy with 5-azacitidine. In summary, 5-azacitidine appears to be a promising alternative therapy for patient with refractory anemia secondary to MDS.

Topics: Aged; Anemia; Antimetabolites, Antineoplastic; Azacitidine; Blood Transfusion; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Male; Myelodysplastic Syndromes; Thrombocytopenia

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.

Topics: Anemia; Antiviral Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Interleukin-11; Neutropenia; Patient Compliance; Polyethylene Glycols; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; Thrombocytopenia

In spite of recent advances in the treatment of myelodysplastic syndromes (MDS), supportive care remains a very important part of the therapy. Red blood cells transfusions are the most important component of this supportive care. They transiently relieve anemia symptoms and alleviate their effects on quality of life and daily functioning. Platelet transfusion therapy is less frequently needed, at least in low-risk MDS. Dealing with an increased risk of infections linked to neutropenia, mainly by broad spectrum antibiotics, is also needed, more often in advanced stages of [dict: MDS] or when the MDS evolves to acute myeloid leukemia. Chronic red blood cell transfusions expose patients to various side-effects, including blood components intolerance reactions and alloimmunization risks, but also increased frequency of iron overload, a more significant problem in low-risk heavily transfused MDS patients, who have prolonged life expectancy. The use of growth factors is becoming a more and more important part of current supportive care. High-dose erythropoietin is able to reduce or suppress red blood cell transfusions needs in selected subgroups of MDS. The short-term use of granulocyte colony-stimulating factor is also often proposed in infections, although not formally established by prospective trials. Although trials of growth factors with thrombopoeitic activity have been performed with interleukin 11 and are underway with thrombopoeitin, none of them are available for routine use.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Growth Substances; Hemorrhage; Humans; Myelodysplastic Syndromes; Neutropenia; Recombinant Proteins; Thrombocytopenia

Haematological disorders of pregnancy are common reasons for referral. It is reasonable then to devote a review to recent publications on these issues.. Several narrative reviews on the management of venous thromboembolic disease in pregnancy provide exceptional guidance. They highlight, however, that most of what is done is still based on opinions from highly qualified people, extrapolated from the non-pregnant literature but not involving randomized trials on pregnant patients. It is apparent that a consensus is nearing on the management of both pregnancy-related thrombocytopenia and idiopathic (immune) thrombocytopenic purpura. Several randomized controlled trials are reported on the treatment of non-deficiency anaemia, using oral iron, intravenous iron and erythropoietin, which contribute to the debate on the appropriate and best intervention for this common problematic issue.. This review demonstrates the need for appropriately sized randomized trials on haematological issues in pregnancy. With heparin becoming the most common medication being administered prophylactically and therapeutically in pregnancy, it is important that quality trials are performed to guide its sensible utilization.

Topics: Anemia; Erythropoietin; Female; Heparin; Humans; Iron, Dietary; Pregnancy; Pregnancy Complications, Hematologic; Prenatal Care; Prenatal Diagnosis; Randomized Controlled Trials as Topic; Thrombocytopenia; Thromboembolism

The liver plays an important role in the production of haemopoietic hormones. It acts as the primary site of synthesis of erythropoietin (EPO) in the fetal stage, and it is the predominant thrombopoietin (TPO)-producing organ for life. In contrast to that of EPO and other liver proteins, the hepatic synthesis of TPO is influenced little by external signals. Hepatocytes express the TPO gene in a constitutive way, i.e. irrespective of the level of platelets in blood. Megakaryocytes and platelets remove the hormone from blood by means of their high-affinity TPO receptors. Normally, the plasma level of TPO is relatively low ( approximately 10(-12) mol/l). However, in thrombocytopenic states due to marrow failure or bleeding, the concentration of circulating TPO may increase greatly. The simple feedback regulation by TPO and its target cells is efficient in maintaining constant platelet numbers in healthy people. Persisting thrombocytopenia develops only in severe liver or marrow failure. On the other hand, an increase in circulating TPO and interleukin 6 (IL-6) may cause reactive thrombocytosis in inflammatory diseases, including cancer. The indications for recombinant human thrombopoietin (rHuTPO) therapy and its impact on transfusion medicine are still under investigation.

Topics: Animals; Clinical Trials as Topic; Erythropoietin; Hematopoiesis; Hormone Replacement Therapy; Humans; Liver; Liver Diseases; Neoplasms; Recombinant Proteins; Thrombocytopenia; Thrombocytosis; Thrombopoietin

Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Azacitidine; DNA, Neoplasm; Erythropoietin; Hematologic Neoplasms; Humans; Recombinant Proteins; Thrombocytopenia

Molecular targeting of novel therapies has the promise of inducing very specific biologic effects. In clinical hematology and oncology, molecular targeting of specific cell surface receptors with erythropoietin, G-CSF, or GM-CSF has been used to stimulate erythropoiesis and granulopoiesis, respectively. Although anemia and neutropenia can be corrected with targeted therapy, safe and effective treatment of thrombocytopenia remains an unmet medical need. While platelet transfusions still represent the standard of care for severe thrombocytopenia, there are several negative aspects associated with their use, including issues of availability, transient effectiveness, costs, adverse effects, negative perception by patients, and infection considerations. Despite extensive investigations of cytokines which act primarily on primitive levels of hematopoiesis, pharmacologic interventions to date have failed to elevate platelet counts in a reliable, highly effective, and well-tolerated fashion. Recombinant human interleukin-11 has been approved by the U.S. Food and Drug Administration for the treatment of chemotherapy-induced thrombocytopenia but has only modest efficacy and significant side effects. The identification of c-Mpl as the thrombopoietin receptor has opened new avenues for the therapeutic manipulation of thrombopoiesis. The development of specific c-Mpl ligands, including recombinant human thrombopoietin (rHuTPO), has allowed investigators to target this receptor for the treatment of chemotherapy-induced thrombocytopenia and other medical disorders characterized by extremely low platelet counts. As a potent stimulator of platelet production, rHuTPO has the potential to reduce the need for platelet transfusions and their attendant complications.

Topics: Cytokines; Erythropoietin; Humans; Interleukin-11; Thrombocytopenia; Thrombopoietin

Topics: Anemia; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Radiotherapy; Thrombocytopenia

Topics: Blood Platelets; Cell Division; Erythropoietin; Humans; Protein Conformation; Thrombocytopenia; Thrombopoietin

Platelets, an integral component of hemostasis, are produced by megakaryocytes derived from the differentiation of pluripotent stem cells in the bone marrow or spleen. After decades of study, the regulation of this process is still not well understood. However, the recent cloning and characterization of thrombopoietin, a ligand for the receptor encoded by the c-mpl proto-oncogene, provides new insights into the humoral regulation of megakaryocytopoiesis and platelet production. Consistent with the proposed role as a major physiological regulator of megakaryocytopoiesis, thrombopoietin has potent effects on megakaryocytopoiesis in vitro and in vivo. In addition to the original supposition that thrombopoietin functions as a late-acting megakaryocyte maturation factor, recombinant thrombopoietin proves also to be a potent stimulator of hematopoietic progenitor cells, inducing them to undergo proliferation and differentiation into megakaryocytic colonies. When administered to mice, thrombopoietin causes an increase in peripheral platelet numbers to previously unattainable levels within a few days. Studies of the efficacy of thrombopoietin are underway. It is envisaged that this new cytokine will have widespread applications as a therapeutic agent for the management of bleeding due to thrombocytopenias, in particular those resulting from cancer chemo- or irradiation therapy.

Topics: Animals; Chromosome Mapping; Cloning, Molecular; Cytokines; Erythropoietin; Hematopoiesis; Humans; Ligands; Molecular Structure; Neoplasm Proteins; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogenes; Receptors, Cytokine; Receptors, Immunologic; Receptors, Thrombopoietin; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

The bleeding time is prolonged in anemic patients independent of their platelet count and is shortened by elevating the hematocrit. It is theorized that an increase in circulating red blood cells increases platelet radial movement and interaction with endothelium. Platelet dysfunction in uremia is well known but poorly understood. Anemia is one contributory factor; others may involve storage pool deficiency, increased vessel wall prostaglandin production, and abnormal platelet arachidonic acid metabolism. Ameliorating anemia with red blood cell transfusions has been shown to shorten the bleeding time without affecting other platelet function values. Recently, recombinant human erythropoietin has been shown to shorten the bleeding time, with a parallel rise in hematocrit level to 30%. Clinicians should be aware that a diminished hematocrit may contribute to the bleeding tendency already present in patients with thrombocytopenia.

Topics: Anemia; Bleeding Time; Blood Platelets; Erythropoietin; Hematocrit; Humans; Megakaryocytes; Platelet Adhesiveness; Thrombocytopenia; Uremia

I have reviewed areas of development in the use of blood and blood products, placing emphasis on the complications of transfusion, particularly transmission of infection. Alloimmunization in relation to transfusion of red cells and platelets has been covered and suggestions for reducing this problem assessed. The potential methods of avoiding the infective complications have been discussed including the screening of blood for infective agents, the virucidal treatment of blood products during the manufacturing process and white cell depletion. The use of recombinant DNA technology to produce coagulation factors offers the possibility of further reducing infective risks. An area of clinical promise is the use of haematopoietic growth factors to treat bone marrow failure, either congenital or acquired, such as the myelosuppressive effects of cancer chemotherapy, and reduce reliance on blood products. The aim of the chapter is to encourage the rational use of a limited resource by considering the risks inherent in transfusion and alternative strategies. In doing this it is important to audit current and future practice, and it is suggested that reference is made to the suggestions of Hume (1989) for quality assessment and assurance in paediatric transfusion medicine.

Topics: Acquired Immunodeficiency Syndrome; Blood Coagulation Factors; Blood Group Antigens; Blood Platelets; Blood Specimen Collection; Blood Transfusion; Blood Transfusion, Intrauterine; Child; Child, Preschool; Colony-Stimulating Factors; Erythrocyte Transfusion; Erythropoietin; Female; Fetal Blood; Fetal Diseases; Hemoglobinopathies; Humans; Immunization; Immunization, Passive; Incidence; Infant; Neoplasm Recurrence, Local; Platelet Transfusion; Pregnancy; Pregnancy Complications, Hematologic; Prenatal Diagnosis; Thrombocytopenia; Transfusion Reaction; Virus Diseases

Topics: Animals; Blood Viscosity; Cardiovascular Diseases; Central Nervous System Diseases; Erythrocyte Deformability; Erythropoietin; Female; Fetal Hypoxia; Fetofetal Transfusion; Fetomaternal Transfusion; Fetus; Follow-Up Studies; Gastrointestinal Diseases; Genital Diseases, Male; Global Health; Growth Disorders; Hematocrit; Humans; Hyperbilirubinemia; Hypocalcemia; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Kidney Diseases; Male; Mental Disorders; Polycythemia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy in Diabetics; Prognosis; Respiration Disorders; Sheep; Thrombocytopenia

Topics: Animals; Bone Marrow Cells; DNA; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Megakaryocytes; Mice; Thrombocytopenia; Thrombopoietin

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Volume; Child; Deficiency Diseases; Erythropoietin; Hemorrhage; Hookworm Infections; Humans; Iron; Iron Deficiencies; Megakaryocytes; Thrombocytopenia; Thrombocytosis

Topics: Androgens; Animals; Blood Platelets; Busulfan; Cell Nucleus; Cytoplasm; Diploidy; Erythropoietin; Estrogens; Female; Hematopoietic Stem Cells; Humans; Kinetics; Male; Megakaryocytes; Mitosis; Mononuclear Phagocyte System; Platelet Transfusion; Polyploidy; Spleen; Thrombocytopenia; Thrombocytosis; Thrombopoietin; Time Factors; Transplantation, Homologous

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.

Topics: Aged; Antineoplastic Agents; Area Under Curve; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Humans; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Risk; Severity of Illness Index; Thalidomide; Thrombocytopenia; Treatment Outcome

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Neutrophils; Platelet Count; Recombinant Proteins; Thrombocytopenia; Treatment Outcome; Tretinoin; Young Adult

To compare the number and volume of red blood cell transfusions (RBCTs) in very low birth weight infants under restrictive red blood cell transfusion guidelines with and without erythropoietin administration.. In a controlled clinical trial conducted at the neonatal intensive care unit of Alzahra Hospital, Isfahan, Iran, between April 2002 to April 2004, 60 premature infants with gestational age up to 34 weeks, birth weight up to 1500 g, and postnatal age between 8 and 14 days were included. The newborns were randomized into 2 groups: Group 1 received 3 doses of 400 IU/kg erythropoietin per week for 6 weeks, and Group 2 received no treatment aside from their conventional medications.. The 2 groups did not differ significantly with respect to their mean gestational age, birth weight and hematocrit at the study entry. Fewer transfusions were administered to those receiving erythropoietin (26.7% versus 50%, p=0.03), but there was no statistically significant difference between groups with respect to volume of transfusion. Compared with the placebo group, the infants receiving erythropoietin had a higher mean hematocrit (34% +/- 4.3 versus 29% +/- 5.9, p<0.001) and absolute reticulocyte count (57 +/- 19 versus 10 +/- 4.8 x 106, p<0.001) at the end of the study. We found no significant difference in the incidence of thrombocytopenia and leukopenia between the 2 groups.. We conclude that when the restrictive RBCT guidelines were followed, treatment with erythropoietin can be useful in reduction of the number of RBCTs.

Topics: Erythrocyte Transfusion; Erythropoietin; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Iran; Leukopenia; Practice Guidelines as Topic; Recombinant Proteins; Thrombocytopenia

Erythropoietin (EPO) not only stimulates erythropoiesis but also thrombopoiesis. As pegylated-interferon-alpha(PEG-IFN-alpha)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-alpha induced thrombocytopenia. Further, we hypothesize that EPO increases platelet reactivity and protease activated receptor 1 (PAR-1) expression during combination antiviral therapy.. Forty patients with chronic hepatitis C received either 10,000 IU EPO 3 x/week or placebo in a randomized, placebo-controlled, double-blinded fashion for 4 wk and combination antiviral therapy with PEG-IFN-2a and ribavirin.. EPO alleviated the decrease in hemoglobin during combination antiviral therapy with ribavirin (10%vs 20%, p < 0.0001). Platelet counts decreased stronger in EPO than in placebo group on day 28 (p= 0.007). EPO induced a 40% increase in PAR-1 (p < 0.0001), which was accompanied by 100% increase in platelet reactivity (p < 0.0001). PFA-100 platelet plug formation time and PEG-IFN-alpha-induced vWF-increase were not different between study groups.. Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-alpha induced thrombocytopenia after the first 4 wk of combination therapy. EPO caused PAR-1 receptor upregulation on platelets, which promoted an increase in platelet reactivity without affecting PFA-100 platelet plug formation time. EPO is not a useful option for short-term support of platelet production during antiviral therapy.

Topics: Adult; Antiviral Agents; Blood Cell Count; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; P-Selectin; Polyethylene Glycols; Receptor, PAR-1; Recombinant Proteins; Ribavirin; Thrombocytopenia

Patients with liver cirrhosis have a complex haemostasis disturbance including thrombocytopenia and abnormal bleeding time. Erythropoietin is the primary stimulator for erythrocyte production and also induces megakaryocyte formation. In healthy men erythropoietin increased platelet count and platelet reactivity.. As patients with liver cirrhosis often undergo invasive procedures, we were interested to study whether erythropoietin could improve platelet function in addition to thrombocytopenia.. In total, 22 thrombocytopenic (platelet counts < 120 g/L) patients with alcoholic liver cirrhosis received either 100 IE/kg erythropoietin or placebo on days 1, 3 and 5 in a 2:1 randomized, placebo-controlled double-blind fashion. Platelet counts and platelet reactivity (activator-stimulated expression of P-selectin on platelets measured by flow cytometry) were determined on study days 1, 3, 5 and 9.. Median platelet count was 80 g/L which is borderline for major elective surgical interventions. Baseline values were not different between groups (P > 0.05). Treatment with erythropoietin increased platelet count by 25% (P = 0.01) and platelet reactivity twofold (P < 0.01) vs. baseline. The increase in platelet count vs. baseline was more pronounced in patients with platelet counts <80 g/L. No significant effect was observed in the placebo group.. Treatment with erythropoietin significantly increased platelet counts and platelet reactivity in patients with alcoholic liver cirrhosis. Preoperative treatment with erythropoietin is therefore expected to yield higher platelet levels and better platelet function.

Topics: Adult; Bleeding Time; Blood Platelets; Double-Blind Method; Erythropoietin; Female; Humans; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Platelet Count; Reticulocyte Count; Reticulocytes; Thrombocytopenia

Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 microg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states.. Our preliminary experience with IL-11 at doses of 50 microg/kg/d suggested that patients with bone marrow failure developed significant peripheral and pulmonary edema after the prolonged dosing necessary for treating these conditions. We, therefore, initiated a study of low-dose IL-11 (starting dose, 10 microg/kg/d).. Sixteen patients were assessable for response. Six patients had diploid cytogenetics; the others had a variety of chromosomal abnormalities. Six (38%) of 16 patients showed a platelet response to IL-11, and two had a multilineage response (to IL-11 alone, n = 1; to IL-11 plus G-CSF and erythropoietin, n = 1). The median increase in peak platelet counts was 95 x 10(9)/L above baseline in the responders (range, increase of 55 x 10(9)/L to 130 x 10(9)/L above baseline). Responders included five of 11 patients with myelodysplasia and one of four patients with aplastic anemia. Response durations were 12, 13, 14+, 25, 30, and 30+ weeks. Side effects of IL-11 were mild (peripheral edema, n = 7; conjunctival injection, n = 7; myalgia, n = 1; all grade 1). Seven patients had no side effects.. Our pilot study suggests that administration of low-dose IL-11 (10 microg/kg/d) can raise platelet counts without significant toxicity in selected thrombocytopenic patients with bone marrow failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bone Marrow Cells; Child; Child, Preschool; Drug Administration Schedule; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-11; Karyotyping; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Platelet Count; Thrombocytopenia

To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count < or = 85,000/microliters were studied. Either a short-term course (7-20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to > or = 100,000/microliters or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70,000 +/- 11,184 to 101,250 +/- 37,625/microliters), while no difference was noted in the placebo group (70,714 +/- 9928 vs 70,000 +/- 10,231/microliters). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Student's t-test, t = -3.80, p < 0.005) and to the results of treatment in the placebo group (unpaired Student's t-test, t = 2.71, p < 0.02). Eight out of 12 recombinant human erythropoietin-treated patients (66%) reached > or = 100,000/microliters platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58,500 +/- 7937 vs 75,750 +/- 7498/microliters, t = -3.69, p = 0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson chi 2 = 4.687, p = 0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Platelets; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Liver Diseases; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia

The introduction of carboplatin as a replacement for cisplatin into treatment strategies against ovarian cancer has ameliorated major toxicities related to cisplatin, but carboplatin-evoked myelosuppression requires further study, especially since the addition of growth factors for bone marrow and hematologic support has been introduced into clinical practice. Since higher doses of platinating agents seem to be related to higher response rates, the protective effect of interleukin-3 on 800 mg carboplatin, a twofold increment over the usual dose, was studied. A modest myeloprotective potency was documented in the second treatment cycle of this aggressive chemotherapy program, but this effect tapered away in subsequent treatment courses, which occasionally included severe side effects (eg, headache, kidney function impairments). Another study addressed the anemia frequently observed with both cisplatin- and carboplatin-based treatment regimens in ovarian cancer, which is probably related to low erythropoietin levels. Very preliminary analysis of an ongoing phase III trial studying two erythropoietin doses given continuously subcutaneously versus a retrospective analysis of a "control group" (drawn from historical data on the occurrence of anemia in cisplatin- and/or carboplatin-treated patients) has shown beneficial effects of erythropoietin during treatment with these platinating agents.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Erythropoietin; Female; Humans; Interleukin-3; Middle Aged; Neutropenia; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

We describe herein the case of a 65-year-old patient on chronic hemodialysis with a medical history of idiopathic thrombocytopenia who experienced numerous episodes of severe thrombocytopenia with no specific diagnosis. Further analysis of the evolution of the platelet count showed that cyclic thrombocytopenia occurred after each injection of recombinant erythropoietin (rHu-EPO). Exploration of the involved mechanisms revealed the presence of a rHu-EPO-dependent anti-GPIV/IIIb antibody associated with a significant increase in GPIV/IIIb expression on her platelets after the addition of rHu-EPO. EPO was discontinued and the patient was treated with roxadustat with favorable results on her hemoglobin and platelet counts.

Topics: Aged; Epoetin Alfa; Erythropoietin; Female; Humans; Recombinant Proteins; Renal Dialysis; Thrombocytopenia

Erythropoietin seems to play an important role in the regulation of fetal hypoxemia. The present prospective study was designed to determine if changes in erythropoietin levels can be found in fetuses with severe early-onset growth restriction and hemodynamic compromise.. Erythropoietin, hemoglobin, hematocrit, platelet counts, normoblasts, lacate, arterial and venous blood gasses in the umbilical cord were determined in 42 fetuses with fetal growth restriction (IUGR) with absent (zero-flow) and 26 IUGR fetuses with retrograde end-diastolic flow (reverse-flow) in the umbilical artery. Color Doppler measurements were performed on the middle cerebral artery (PI) and ductus venosus [(S-a)/D and (S-a)/Vmean]. Erythropoietin concentrations were significantly lower in the zero-flow group (median: 128.0 mU/mL; range: 60.3-213 mU/mL) compared with the reverse-flow group (median: 202.5 mU/mL; range: 166-1182 mU/mL). Significant differences in median lactate concentrations were observed between the zero-flow group: 3.28 mmol/L (range; 2.3-4.7 mmol/L), and reverse-flow group: 5.6 mmol/L (range: 3.8-7.5 mmol/L). Fetuses with reverse-flow had significantly lower median platelet counts than fetuses with zero-flow (74 vs. 155/μL) and significantly lower normoblast counts (63 vs. 342/100 WBC).. Fetuses with severe IUGR due to chronic placental insufficiency and absent or reversed flow in the umbilical artery show increased erythropoietin levels.

Topics: Blood Flow Velocity; Erythropoietin; Female; Fetal Growth Retardation; Humans; Hypercapnia; Hypoxia; Platelet Count; Pregnancy; Prospective Studies; Thrombocytopenia; Ultrasonography, Doppler, Color; Ultrasonography, Prenatal; Umbilical Arteries

Topics: Adult; Anemia, Iron-Deficiency; Case-Control Studies; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Middle Aged; Platelet Count; Thrombocytopenia

Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1β, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Caspase 3; Cytokines; Disease-Free Survival; Erythropoietin; Hematopoiesis; Hemorrhage; Inflammation; Kidney; Lethal Dose 50; Leukopenia; Male; Mice; MicroRNAs; NF-kappa B; Radiation Injuries; Thrombocytopenia; Water

Topics: Aged; Diabetes Complications; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Platelet Count; Thrombocytopenia

Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; Cells, Cultured; Erythropoietin; Female; Fibroblasts; Hematopoiesis, Extramedullary; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Keratinocytes; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Polycythemia; Procollagen-Proline Dioxygenase; Severity of Illness Index; Thrombocytopenia

Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouse Hbb-b2 gene, denoted Plt12, that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen and Plt12 mutant mice exhibited reduced partial pressure of O(2) in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygous Hbb-b2(Plt12/Plt12) mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation of Hbb-b2(Plt12/Plt12) mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes in Hbb-b2(Plt12/Plt12) mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. The Plt12 mouse is a model of high O(2)-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia.

Topics: Animals; Blood Cell Count; Blood Gas Analysis; Erythropoiesis; Erythropoietin; Half-Life; Hemoglobins, Abnormal; Male; Megakaryocytes; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mutation; Oxygen; Polycythemia; Splenomegaly; Thrombocytopenia

The DEAH helicase RHAU (alias DHX36, G4R1) is the only helicase shown to have G-quadruplex (G4)-RNA resolvase activity and the major source of G4-DNA resolvase activity. Previous report showed RHAU mRNA expression to be elevated in human lymphoid and CD34(+) BM cells, suggesting a potential role in hematopoiesis. Here, we generated a conditional knockout of the RHAU gene in mice. Germ line deletion of RHAU led to embryonic lethality. We then targeted the RHAU gene specifically in the hematopoiesis system, using a Cre-inducible system in which an optimized variant of Cre recombinase was expressed under the control of the Vav1 promoter. RHAU deletion in hematopoietic system caused hemolytic anemia and differentiation defect at the proerythroblast stage. The partial differentiation block of proerythroblasts was because of a proliferation defect. Transcriptome analysis of RHAU knockout proerythroblasts showed that a statistically significant portion of the deregulated genes contain G4 motifs in their promoters. This suggests that RHAU may play a role in the regulation of gene expression that relies on its G4 resolvase activity.

Topics: Anemia, Hemolytic, Congenital; Animals; Bone Marrow Transplantation; Cell Cycle; Crosses, Genetic; DEAD-box RNA Helicases; Embryonic Development; Erythroblasts; Erythropoietin; Genes, Lethal; Genes, Synthetic; Green Fluorescent Proteins; Hematopoiesis; Leukopenia; Mice; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; Protein Folding; Proto-Oncogene Proteins c-vav; Radiation Chimera; Recombinases; Thrombocytopenia

Recombinant human erythropoietin (rhEPO) has been successfully used for correcting renal anemia. However, recent studies have raised some concerns about the safety of rhEPO treatment due to its immunogenic side effect - pure red cell aplasia (PRCA). We now report a case of development of anti-EPO neutralizing antibodies (Abs) implicated in thrombocytopenia as well as erythrocytopenia. A 35-year-old man had a history of administering rhEPO (epoetin alfa, epoetin beta and darbepoetin alfa) for 2years to treat renal anemia. The hematological parameters were collected. Anti-EPO, anti-platelet, and anti-thrombopoietin (TPO) Ab assays were performed to test the presence of autoreactive Abs. After performing antibody assays due to severe resistance to rhEPO treatment, a high titer of anti-EPO neutralizing Abs was detected. However, unexpectedly, this patient also showed thrombocytopenia rather than PRCA. We investigated the cause of the marked thrombocytopenia and found anti-TPO Abs in patient serum. To our best knowledge, this is the first report of the development of anti-TPO Abs during rhEPO treatment for anemia.

Topics: Adult; Antibodies, Neutralizing; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Thrombocytopenia; Thrombopoietin; Treatment Outcome

Topics: Aged; Combined Modality Therapy; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Ferric Compounds; Hematinics; Hemostatic Techniques; Humans; Jehovah's Witnesses; Male; Middle Aged; Multiple Myeloma; Patient Acceptance of Health Care; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Serum Albumin; Sodium Chloride; Thrombocytopenia; Transplantation, Autologous

The majority of patients with myelodysplastic syndromes (MDS) are older, and the incidence of these diseases is rising as the population ages. Clinicians are often uncertain about how to identify patients who may benefit from specific treatment strategies. The International Prognostic Scoring System is a widely used tool to assess risk of transformation to leukemia and guide treatment decisions, but it fails to take into account many aspects of treating elderly patients, including comorbid illness, secondary causes of MDS, prior therapy for MDS, and other age-related health, functional, cognitive, and social problems that affect outcome. Patients with lowrisk disease traditionally have been given supportive care, but evidence is increasing that treatment with lenalidomide or methyltransferase inhibitors may influence the natural history of the disease and should be used in conjunction with supportive-care measures. Supportive care of these patients also could be improved to enhance their quality of life and functional performance.

Topics: Aged; Anemia; Antineoplastic Agents; Azacitidine; Decitabine; Erythrocyte Transfusion; Erythropoietin; Humans; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Neutropenia; Thalidomide; Thrombocytopenia

Physiopathology of anaemia and thrombocytopaenia in children with malignancy: the role of erythropoietin and thrombopoietin. The aim of our work was to determine the role of an impaired erythropoietin (EPO) and thrombopoietin (TPO) production in development of, respectively, the anaemia and thrombocytopaenia in children with malignancy. Simultaneous dosage of EPO and of serum transferrin receptor have shown that anaemia in these patients is of central origin but related to a blunted EPO production. The same observation has been made in children at diagnosis either with acute leukaemia or solid tumour as well as during chemotherapy. In patients under maintenance chemotherapy for acute leukaemia, using long-term bone marrow cultures, we could detect an impaired supportive capacity of bone marrow micro-environment for erythropoiesis. The last part of this work has shown that thrombocytopaenia associated with acute leukaemia in children is accompanied by very high TPO levels as observed in other thrombocytopaenia of central origin, excepted in patients with acute leukaemia of myeloid origin. In these patients, TPO levels are inappropriately low in most cases. The low TPO levels are related to the presence of TPO receptor-expressing myeloid leukaemic cells, suggesting that TPO is "consumed" by blast cells expressing a functional TPO receptor.

Topics: Anemia; Child; Erythropoietin; Humans; Neoplasms; Thrombocytopenia; Thrombopoietin

Patients with cancer-related anemia have an inadequate Epo response that is further impaired by cancer treatments such as chemotherapy. Significant number of studies have demonstrated that treatment of anemia in cancer patients using recombinant human EPO(rHuEPO, epoetin alfa) significantly increases hemoglobin(Hb) levels,reduces transfusion requirements,and improves quality of life,particularly by relieving fatigue. However,the findings of several studies have raised the possibility of an adverse effect of thromboembolism. The American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. In cancer patients, the risk of bleeding depends not only on the platelet count, but also on the underlying disease, in accordance with coagulation defects. The cause of thrombocytopenia must be established prior to platelet transfusion since platelet transfusions may be relatively contraindicated in certain conditions e. g., heparin-induced thrombocytopenia(HIT), and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome(TTP/HUS).

Topics: Anemia; Disseminated Intravascular Coagulation; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Platelet Transfusion; Quality of Life; Recombinant Proteins; Thrombocytopenia

We examined whether women aged 60 years or older with ovarian cancer who were treated with surgery and postoperative chemotherapy are at higher risk of developing grade 4 hematological toxicity. Seventy-five patients were included: 34 patients aged < 60 years (group I) were compared with 41 patients aged > or =60 years (group II) after postoperative treatment with single-agent carboplatin or carboplatin/taxane combination chemotherapy. Secondary prophylaxis with granulocyte colony-stimulating factors was performed to avoid dose reduction and chemotherapy delay. A total of 450 chemotherapy cycles was completed. Anemia and thrombocytopenia were mild in both groups. Overall, grade 4 neutropenia developed in 41% (group I) and in 49% (group II) (p=0.51). Febrile neutropenia occurred in 12% and 2%, respectively (p=0.17). The carboplatin/taxane combination was associated with grade 4 neutropenia in 42% (group I) and 58% (group II) (p=0.21). Women > or =60 years are not at higher risk of developing severe myelotoxicity than their younger counterparts, particularly after treatment with carboplatin/taxane combination chemotherapy.

Topics: Adult; Age Factors; Aged; Anemia; Antineoplastic Agents; Carboplatin; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Middle Aged; Neutropenia; Ovarian Neoplasms; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Risk Factors; Taxoids; Thrombocytopenia

Although unfractionated heparin is the most commonly used anticoagulant for hemodialysis and has been associated with bleeding episodes, a more devastating complication that can occur is heparin-induced thrombocytopenia (HIT). It is believed that HIT type II is much more dangerous than type I, because HIT type II is associated with thromboembolic complications whereas there are no such complications in HIT type I. However, increased clot formation in the extracorporeal circuit during hemodialysis with unfractionated heparin is sometimes experienced by not only patients with HIT type II but also those with HIT type I. Three patients with HIT type I are presented who suffered from clot formation during hemodialysis, and in whom 81 mg of aspirin and/or cessation of heparin was prescribed. All three patients had received recombinant human erythropoietin (rHuEpo). Both heparin and rHuEpo induce enhanced platelet aggregation; therefore, it is possible that even HIT type I patients may suffer clot formation in the extracorporeal circuit due to platelet activation via the synergistic effects of unfractionated heparin and rHuEpo.

Topics: Aged; Drug Synergism; Erythropoietin; Female; Heparin; Humans; Male; Middle Aged; Platelet Aggregation; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombosis

Dysregulated erythropoietin (EPO) plasma levels may play a role in the pathophysiology of chronic liver disease (CLD) because chronic anaemia is frequently observed in patients with liver cirrhosis. We aimed to identify the factors contributing to EPO regulation in patients with CLD.. Plasma EPO concentrations were correlated with clinical and laboratory parameters in 111 CLD patients and 220 healthy controls.. Anaemia, though generally mild, was common in CLD patients, and thrombocytopenia and previous bleeding episodes were observed in two-thirds of the patients. Plasma EPO levels were significantly elevated in CLD patients (P < 0.001). EPO increased according to Child's stages of cirrhosis, independently of the aetiology of CLD. EPO correlated with haemoglobin (r= -0.498, P < 0.001). Additionally, EPO independently correlated with markers of liver dysfunction, e.g. prothrombin time, albumin concentration or cholinesterase activity, and platelet count. EPO was also significantly elevated in patients with a current bleeding tendency and with prior gastrointestinal haemorrhages. EPO levels were increased in patients with impaired pulmonary function, e.g. decreased diffusion capacity, vital capacity or hyperventilation. Interestingly, plasma interleukin-6 (IL-6) concentrations positively correlated with EPO (r=0.277, P = 0.003), suggesting a possible mechanism of EPO upregulation in patients with CLD through IL-6 dependent pathways, e.g. binding of STAT transcription factors in the putative EPO promoter region.. EPO is upregulated in patients with chronic liver diseases in response to anaemia, bleeding complications, impaired pulmonary function, thrombocytopenia and liver dysfunction. IL-6 dependent pathways could be involved in mediating elevated EPO levels in CLD patients.

Topics: Adolescent; Adult; Aged; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemorrhage; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Respiratory Function Tests; Severity of Illness Index; Thrombocytopenia; Up-Regulation

Current therapy for the treatment of hepatitis C virus (HCV) infection is standard interferon (IFN) or pegylated interferon (PEG-IFN) in combination with ribavirin (RBV). Hematologic side effects (neutropenia, thrombocytopenia, anemia) are a major reason for dose reduction of anti-HCV therapy. Because treatment adherence and maintenance of IFN or PEG-IFN and RBV doses have been shown to be important in achieving a sustained virologic response, appropriate management of hematologic side effects might play a substantial role in optimizing treatment outcomes. Neutropenia and thrombocytopenia are usually managed by IFN or PEG-IFN dose reduction; the role of hematopoietic growth factors to ameliorate these side effects needs further evaluation, but some studies suggest granulocyte colony-stimulating factor (G-CSF) may be useful in the management of IFN/PEG-IFN-associated neutropenia. Anemia is primarily due to RBV-induced hemolytic anemia, but IFN/PEG-IFN also suppresses bone marrow erythroid precursors. Treatment-induced anemia has usually been managed by RBV dose reduction or discontinuation. However, recent studies suggest that epoetin alfa can increase hemoglobin levels and facilitate maintenance of RBV dosage in patients with chronic hepatitis C who became anemic during standard combination therapy. Results of a randomized, randomized, double-blind, placebo-controlled trial suggest that epoetin alfa therapy can maintain RBV dosage, increase hemoglobin levels, and improve quality of life in this population. In patients who have chronic hepatitis C who experience hematologic toxicities during standard therapy, the use of hematopoietic growth factors such as epoetin alfa might have the potential to improve treatment adherence rates and allow optimal doses of IFN or PEG-IFN and RBV to be maintained, thereby leading to improved treatment outcomes.

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Hematinics; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.

Topics: Aged; Erythropoietin; Female; Follow-Up Studies; Humans; Hypersplenism; Hypertension; Iron Overload; Liver Cirrhosis; Male; Middle Aged; Phlebotomy; Platelet Count; Retrospective Studies; Thrombocytopenia; Thrombopoietin; Treatment Outcome

We evaluated the concentrations of vascular endothelial growth factor (VEGF) and angiogenin in the umbilical cord blood from 14 fetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm fetuses, from 42 healthy term fetuses, and from 24 term fetuses born to mothers with insulin-treated diabetes. A correlation appeared between VEGF and angiogenin levels (r = 0.44, p = 0.038). The gestational age correlated with both VEGF (r = 0.38, p = 0.0008) and angiogenin levels (r = 0.80, p = 0.0001). The concentration of VEGF was lower in fetuses born to mothers with insulin-treated diabetes than in the healthy term fetuses (p = 0.0028), but this difference was absent for angiogenin (p > 0.05). In conclusion, in umbilical cord plasma, a developmental increase was evident in concentrations of VEGF and angiogenin during the last trimester of gestation. That the umbilical cord VEGF level was lower in term fetuses born to mothers with diabetes than in term fetuses of healthy mothers may be associated with an aberrant fetal vascular development in diabetic pregnancies.

Topics: Diabetes Mellitus, Type 1; Embryonic and Fetal Development; Erythroblastosis, Fetal; Erythropoietin; Female; Fetal Blood; Gestational Age; Humans; Insulin; Isoantibodies; Male; Pregnancy; Pregnancy in Diabetics; Ribonuclease, Pancreatic; Thrombocytopenia; Vascular Endothelial Growth Factor A

Strategies for managing antineoplastic therapy-associated hematopoietic toxicity (thrombocytopenia, neutropenia, and anemia) are discussed. Hemorrhage secondary to decreases in platelets is the major risk posed by chemotherapy-induced thrombocytopenia. Patients with < 20,000 platelets per microliter are at increased risk of bleeding, particularly if they have a history of bleeding associated with this condition. The risks of infection and complications are related to both the severity and duration of neutropenia. The rate of febrile neutropenia with most antineoplastic regimens is < 40%, and routine use of cytokine therapy is probably not cost-effective. The frequency of cancer-related anemia is dependent on the type, stage, and duration of disease. Chemotherapy-induced anemia is affected by the types of agents used, the schedule of drug administration, and the intensity of the regimen. Fatigue is the most common symptom of anemia, being reported by 80-100% of patients undergoing chemotherapy. Although fatigue is a major factor in patients' quality of life, it has often not been treated systematically and aggressively. Anemia used to be treated with transfusions, but therapy with epoetin alfa is showing promise as an alternative. The introduction of epoetin alfa has led to more aggressive treatment. Chemotherapy-induced hematopoietic toxicity is a multifactorial challenge that affects the treatment of oncology patients.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Fatigue; Hematinics; Humans; Neutropenia; Practice Guidelines as Topic; Recombinant Proteins; Severity of Illness Index; Thrombocytopenia

The thrombopoietic status of patients with uremia remains unclear. This issue was addressed with particular reference to marrow megakaryocytopoiesis and endogenous thrombopoietin (TPO) levels. A study was conducted in 114 patients on hemodialysis, 43 patients on continuous ambulatory peritoneal dialysis, and 48 age-matched controls. Reticulated platelets, a marker of marrow megakaryocytopoiesis, were measured by flow cytometry. Serum TPO levels, platelet-associated IgG (PAIgG) levels, and hepatitis C virus (HCV) antibody titers were also measured by enzyme-linked immunosorbent assay. Circulating and reticulated platelet counts were significantly lower in the patients on dialysis than in the controls. Thrombocytopenia (less than 150 x 10(9)/L) was most frequent in the HCV-positive hemodialysis patients, who had a higher incidences and higher PAIgG titers. The following results were obtained in the HCV-negative dialysis patients: (1) platelet counts chronologically decreased with years on hemodialysis; (2) platelet counts were associated with the reticulated platelet counts; (3) serum TPO levels were significantly elevated in the dialysis patients, responding to the decrease of reticulated platelets; (4) hematocrits had a positive correlation with serum TPO levels, and serum TPO levels were significantly higher in the patients on hemodialysis who did not require recombinant human erythropoietin therapy than in the other patients. In conclusion, thrombocytopenia is a frequent finding in patients on dialysis. The failure of megakaryocyte production could be the principal cause of the platelet reduction, and the peripheral destruction and sequestration of platelets may be concomitantly involved. Elevation of serum TPO may in part serve as an aid to erythropoiesis in dialysis patients.

Topics: Adult; Anemia; Antigens, Human Platelet; Autoantibodies; Blood Platelets; Bone Marrow; Erythropoietin; Flow Cytometry; Hematocrit; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Immunoglobulin G; Kidney Failure, Chronic; Megakaryocytes; Middle Aged; Platelet Count; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombopoietin

Topics: Erythropoietin; Female; Humans; Middle Aged; Platelet Count; Radius; Recombinant Proteins; Syndrome; Thrombocytopenia

To define the incidence, course, and etiology of hematologic abnormalities in children on tacrolimus-based immunosuppression, we reviewed records of 106 transplant patients (70 heart, 16 heart and lung, 20 double lung), 0-21 yr of age, who were transplanted at the Children's Hospital of Pittsburgh from 1989 to 1997. Fifty-four of the 106 patients (51%) developed 65 abnormal hematologic episodes (32 anemia, nine neutropenia, nine thrombocytopenia, 15 simultaneous anemia and neutropenia with or without thrombocytopenia). Common etiologies included: infections, post-transplant lymphoproliferative disease, and medications. Eleven episodes (seven anemia, one neutropenia, and three simultaneous anemia and neutropenia) had unclear etiologies and process of elimination suggested an association with tacrolimus. Interventions included filgrastim (effective in 15 of 15 patients, with resolution of neutropenia in a median of 5 days) and epoetin alfa (effective in five of 16 patients, including four of four patients with anemia possibly related to tacrolimus). Five patients (two with neutropenia and three with simultaneous neutropenia and anemia) were switched to cyclosporin A (CsA); rapid resolution occurred in four of the five patients, suggesting a possible association of the hematologic abnormalities with tacrolimus. In summary, hematologic abnormalities are common in children on tacrolimus-based immunosuppression. Most of these hematologic abnormalities are caused by common etiologies; however, a sub-population exists where tacrolimus may be the etiologic agent. Anemia and neutropenia respond to treatment with epoetin alfa and filgrastim. After thorough investigation, a trial switch to CsA may be warranted.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Heart Transplantation; Heart-Lung Transplantation; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Lung Transplantation; Male; Neutropenia; Recombinant Proteins; Retrospective Studies; Tacrolimus; Thrombocytopenia

The response of mice genetically unable to up-regulate GATA-1 expression (GATA-1(low) mice) to acute (phenylhydrazine [PHZ]-induced anemia) and chronic (in vivo treatment for 5 days with 10 U erythropoietin [EPO] per mouse) erythroid stimuli was investigated. Adult GATA-1(low) mice are profoundly thrombocytopenic (platelet counts [x 10(9)/L] 82.0 +/- 28.0 vs 840 +/- 170.0 of their control littermates, P <.001) but have a normal hematocrit (Hct) (approximately.47 proportion of 1.0 [47%]). The spleens of these mutants are 2.5-fold larger than normal and contain 5-fold more megakaryocytic (4A5(+)), erythroid (TER-119(+)), and bipotent (erythroid/megakaryocytic, TER-119(+)/4A5(+)) precursor cells. Both the marrow and the spleen of these animals contain higher frequencies of burst-forming units-erythroid (BFU-E)- and colony-forming units-erythroid (CFU-E)-derived colonies (2-fold and 6-fold, respectively) than their normal littermates. The GATA-1(low) mice recover 2 days faster from the PHZ-induced anemia than their normal littermates (P <.01). In response to EPO, the Hct of the GATA-1(low) mice raised to.68 proportion of 1.0 (68%) vs the.55 proportion of 1.0 (55%) reached by the controls (P <.01). Both the GATA-1(low) and the normal mice respond to PHZ and EPO with similar (2- to 3-fold) increases in size and cellularity of the spleen (increases are limited mostly to cells, both progenitor and precursor, of the erythroid lineage). However, in spite of the similar relative cellular increases, the increases of all these cell populations are significantly higher, in absolute cell numbers, in the mutant than in the wild-type mice. In conclusion, the GATA-1(low) mutation increases the magnitude of the response to erythroid stimuli as a consequence of the expansion of the erythroid progenitor cells in their spleen.

Topics: Anemia; Animals; Bone Marrow Cells; Cell Count; DNA-Binding Proteins; Erythroid Precursor Cells; Erythroid-Specific DNA-Binding Factors; Erythropoietin; Female; Flow Cytometry; GATA1 Transcription Factor; Gene Expression; Hematocrit; Hematopoietic Stem Cells; Immunohistochemistry; Male; Megakaryocytes; Mice; Mice, Inbred C57BL; Mutation; Phenylhydrazines; Platelet Count; Spleen; Thrombocytopenia; Transcription Factors

A 35-year-old female presented with isolated thrombocytopenia of autoimmune origin. One and a half years later, hypoplastic myelodysplastic (MDS) was diagnosed. Following treatment with cyclosporin A, erythropoietin and granulocyte colony-stimulating factor, the patient has achieved a sustained hematological remission which is still ongoing after 3 years. Furthermore, to the best of our knowledge, this is the third case described in the literature where treatment with cytokines alone or in combination with immunosuppressive agents has resulted in a long standing cytogenetic response in MDS.

Topics: Adult; Autoimmune Diseases; Cyclosporine; Disease Progression; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Platelet Count; Remission Induction; Thrombocytopenia

Thrombocytopenia is a substantial clinical problem for patients with myelodysplastic syndromes (MDS). Cytokine treatment for granulocytopenia and anaemia may further reduce the platelet counts. We studied serum thrombopoietin levels (S-TPO) in 52 patients with MDS and 96 healthy controls and related the results to clinical and morphological variables. S-TPO was also assessed after treatment with granulocyte-CSF (G-CSF) and erythropoietin (EPO) in 30 of these patients. S-TPO in MDS was not a normally distributed variable; mean value was 394 pg/ml, SD +/-831 and median value 123 (12-5000 pg/ml). The controls showed lower S-TPO levels than the patients (median 78 pg/ml, P = 0.003) whereas no differences between the MDS subgroups were observed (P = 0.86). Patients with ringed sideroblastic anaemia (RARS) showed the highest platelet counts and higher S-TPO levels than the controls (P = 0.005). No association between platelet counts and S-TPO levels was found in the patients (P = 0.67). TPO levels were generally low in patients with refractory anaemia with an excess of blasts (RAEB), but very high levels were found in five patients. Patients with a high transfusion need had higher S-TPO levels, whereas bone marrow blast counts, cellularity or megakaryocytes showed no correlation with S-TPO. Patients with 5q- showed lower TPO levels than the other patients, indicating that thrombopoietin is not a mediator of thrombocytosis in these cases. Treatment with G-CSF + EPO significantly reduced the platelet counts (P = 0.0002), but this change was not related to significant changes in S-TPO levels or morphology. Patients with RARS and thrombocytosis who normalized their platelet counts showed a concomitant reduction in S-TPO. This may suggest that the increased platelet counts observed in RARS may be caused by increased S-TPO levels. In conclusion, our study shows that platelet, megakaryocyte and thrombopoietin regulation is rather complex in myelodysplastic syndromes and that spontaneous or induced thrombocytopenia are not usually mirrored by increased S-TPO levels.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

Topics: Anemia; Animals; Antineoplastic Agents; Drug Interactions; Erythropoietin; Hemoglobins; Interleukin-12; Mice; Platelet Count; Thrombocytopenia; Tumor Cells, Cultured

We present a case report of a 55-year-old male patient with hypoplastic myelodysplastic syndrome (MDS, refractory anemia) in which a good response to recombinant human erythropoietin (rhEPO) has been maintained for more than 60 months. There is with no evidence of progression to high risk MDS or acute leukemia, although he was predicted to be a low-responder to rhEPO therapy because of very high serum EPO levels (5,260 mU/ml), a history of multiple transfusions, chromosomal abnormalities (47,XY,+8) and severe thrombocytopenia. Since he received rhEPO with no adverse effects, it may be valuable to try rhEPO treatment at least one time for low-risk MDS patients, depending on red cell transfusion requirements.

Topics: Anemia, Refractory; Biopsy, Needle; Bone Marrow; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 8; Erythropoietin; Follow-Up Studies; Humans; Karyotyping; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia

To clarify the role of thrombopoietin (c-Mpl ligand, TPO) in 'hypersplenic' thrombocytopenia, we used an enzyme-linked immunosorbent assay to examine changes in serum TPO levels accompanied with splenectomy in 6 patients with liver cirrhosis, 4 patients with gastric cancer, and 2 patients with lymphoid malignancies. We also measured serum levels of other thrombopoietic cytokines such as interleukin-6 (IL-6) and erythropoietin. Platelet counts reached a maximum at day 14 after splenectomy in all subjects. In patients with liver cirrhosis, a lower elevation of platelet counts was observed compared with that in patients with gastric cancer. Serum TPO levels gradually elevated after splenectomy and reached a maximum 3.5 days after splenectomy in noncirrhotic patients, whereas peak serum TPO levels were delayed until day 7 in the cirrhosis group. IL-6 and erythropoietin showed similar kinetics between cirrhotic and noncirrhotic patients. These findings suggest that transient thrombocytosis after splenectomy may be associated with an alteration in the site of TPO catabolism by platelets from spleen to the blood and that deterioration of TPO production may play a role in thrombocytopenia in liver cirrhosis.

Topics: Adult; Aged; Erythropoietin; Female; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Splenectomy; Thrombocytopenia; Thrombocytosis; Thrombopoietin

Feline thrombopoietin (TPO) was molecularly cloned to establish a basis for cytokine therapy of thrombocytopenia in cats. cDNA clones covering the whole coding sequence of feline TPO were isolated from feline liver. The feline TPO cDNA obtained in this study contained an open reading frame encoding 349 amino acid residues. The predicted amino acid sequence of feline TPO shared 78.7, 69.9, 72.9 and 83.0% similarity with sequences of human, murine, rat and canine TPO, respectively. Four cysteine residues and two of four N-glycosylation sites that are conserved among species were also found at the corresponding positions in feline TPO. The feline TPO cDNA fragment encoding the whole amino acid coding region was recloned into an expression vector, and the resulting vector was transfected into 293T cells using the calcium phosphate method. The supernatant of the transfected 293T cells stimulated the proliferation of a human megakaryoblastic leukemia cell line (UT-7/TPO) cells in a dose dependent manner, indicating that the feline TPO cDNA obtained in this study encodes biologically active feline TPO.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cats; Cell Differentiation; Cell Division; Cloning, Molecular; DNA, Complementary; Dogs; Erythropoietin; Humans; Megakaryocytes; Molecular Sequence Data; Polymerase Chain Reaction; Rats; Thrombocytopenia; Thrombopoietin

Topics: Adolescent; Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Platelet Count; Platelet Transfusion; Recombinant Proteins; Thrombocytopenia

Thrombopoietin, the ligand for the c-mpl receptor, promotes proliferation and maturation of megakaryocytes. An ELISA using a chimaeric receptor, mpl-IgG, for capture, and rabbit antibody to thrombopoietin for detection was developed for the quantitation of thrombopoietin in human serum or plasma. This ELISA preferentially detects full-length thrombopoietin compared to the bioactive N-terminal half of the molecule which has homology to erythropoietin. Thrombopoietin was not detected (< 0.16 ng/ml) in 88/89 healthy individuals. However, elevated thrombopoietin concentrations of up to 3 ng/ml were detected in 59/63 thrombocytopenic patients, including cancer patients following chemotherapy. In cancer patients receiving chemotherapy with (n = 12) or without (n = 6) peripheral blood progenitor cell transplantation, thrombopoietin concentrations varied inversely with platelet counts throughout the treatment period. In general, patients who received myeloablative chemotherapy on days -7 to -2 and peripheral blood progenitor cell transplantation on day 0 had high thrombopoietin levels (0.6-2.9 ng/ml) around day 5. Low platelet counts (< 20 x 10(9)/l) occurred between days 4 and 9. Patients who received high-dose chemotherapy on day 1 (equivalent to day -7 for transplantation patients) to day 6 without transplantation had high thrombopoietin concentrations (1.4-2.3 ng/ml) around day 13 and low platelet counts occurred between days 7 and 17.

Topics: Adult; Aged; Antineoplastic Agents; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Neoplasms; Platelet Count; Thrombocytopenia; Thrombopoietin

Topics: Chronic Disease; Erythropoietin; Humans; Liver Diseases; Recombinant Proteins; Thrombocytopenia

Topics: Erythropoietin; Humans; Liver Diseases; Recombinant Proteins; Thrombocytopenia

Lipid peroxidation, measured by malonyldialdehyde (MDA) and vitamin E in red blood cells (RBC) and plasma, was investigated in 25 hemodialysis (HD) patients before and after 6 months rhEPO therapy. RBC-MDA was significantly elevated, but plasma MDA was in the reference range. After recombinant human erythropoietin (rhEPO) treatment, the MDA level was significantly decreased in both compartments. Marked vitamin E deficiency was established in RBC as well as in plasma. rhEPO therapy restored vitamin E levels in both compartments. Our data suggest a possible positive rhEPO-antioxidant effect in HD patients.

Topics: Adolescent; Adult; Antioxidants; Case-Control Studies; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Plasma; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Vitamin E; Vitamin E Deficiency

A case of adult osteopetrosis Type I was diagnosed in a 22-year-old female. She presented for investigation of anaemia with 'myelophthisic' characteristics and extramedullary haemopoiesis which was resistant to haematinics, nandrolone and low-dose corticosteroids. She became progressively transfusion-dependent with gradually worsening thrombocytopenia. She was successfully treated with recombinant erythropoietin. Anaemia as well as thrombocytopenia were corrected. There appeared to be a synergistic action of erythropoietin with steroids.

Topics: Adult; Anemia; Bone Marrow Diseases; Erythropoietin; Female; Humans; Osteopetrosis; Recombinant Proteins; Thrombocytopenia

Topics: Anemia; Bone and Bones; Erythropoietin; Female; Humans; Middle Aged; Radionuclide Imaging; Receptors, Granulocyte Colony-Stimulating Factor; Thrombocytopenia

Evaluation of pharmacologic agents that stimulate fetal hemoglobin production has been done mainly in baboons and macaques. We investigated whether results in transgenic mice can predict the stimulation of fetal hemoglobin in primates, by testing gamma globin induction in response to a new ribonucleotide reductase inhibitor, Didox. A transgenic mouse line carrying the human A gamma gene linked to a locus control region cassette was used. Treatment of transgenic mice with Didox resulted in induction of gamma gene expression as documented by an increase in F reticulocytes and F cells and an elevation of gamma/gamma + beta biosynthetic ratio. Similarly, administration of Didox to a baboon in the nonanemic and chronically anemic state resulted in induction of gamma gene expression as shown by increases in F reticulocytes, F cells, and Hb F. These results suggest that the muLCR-A gamma transgenic mice can be used to screen new pharmacologic compounds for gamma globin inducibility.

Topics: Anemia; Animals; Chemical and Drug Induced Liver Injury; Erythropoietin; Fetal Hemoglobin; Gene Expression; Humans; Hydroxamic Acids; Leukopenia; Mice; Mice, Transgenic; Recombinant Proteins; Reticulocytes; Ribonucleotide Reductases; Thrombocytopenia

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Drug Synergism; Erythropoietin; Female; Hematopoiesis; Hematopoietic Stem Cells; Heme; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neutropenia; Thrombocytopenia; Weight Loss; Zidovudine

To assess the efficacy and the mechanism of action of alpha-interferon (alpha-IFN) in the treatment of HIV-related thrombocytopenia.. Thirteen HIV-positive subjects [nine men and four women with severe thrombocytopenia (platelets, < or = 30 x 10(9)/l)] were treated with alpha-IFN 2b alone at a dose of 3 x 10(6) U three times a week for 5 weeks. Haematological parameters, platelet kinetic and bone-marrow myeloid progenitor cultures [megakaryocyte colony-forming units (CFU-MK); granulocyte macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E)] were evaluated before and after treatment in responsive subjects.. Seven out of 13 subjects showed a partial response (platelets, 50-149 x 10(9)/l) after alpha-IFN 2b therapy. Platelet survival as evaluated by 111In-oxine significantly increased, while platelet turnover showed a slight but not statistically significant increase after treatment. The growth of bone-marrow myeloid progenitor cells decreased after alpha-IFN 2b therapy, again without statistical significance.. alpha-IFN 2b may increase the platelet count in HIV-positive subjects with severe symptomatic thrombocytopenia by prolonging platelet survival. The immunomodulatory and antiviral action of this drug may be responsible for prolonged platelet survival.

Topics: Adult; AIDS-Related Complex; Autoimmune Diseases; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Drug Evaluation; Erythroid Precursor Cells; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Interferon alpha-2; Interferon-alpha; Interleukin-3; Male; Megakaryocytes; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombocytopenia

Topics: Animals; Blood Platelets; Erythropoietin; Hematocrit; Mice; Platelet Count; Splenectomy; Thrombocytopenia

Topics: Anemia; Blood Platelets; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Leukopenia; Recombinant Proteins; Renal Dialysis; Thrombocytopenia

PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy.. We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously).. In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin.. Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bacterial Infections; Bone Marrow; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hemoglobins; Humans; Injections, Subcutaneous; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neutropenia; Neutrophils; Platelet Count; Recombinant Proteins; Thrombocytopenia; Time Factors

Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO-injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.

Topics: Animals; Blood Platelets; Blood Volume; Bone Marrow; Erythrocyte Count; Erythropoietin; Hematocrit; Immune Sera; Male; Megakaryocytes; Mice; Mice, Inbred C3H; Platelet Count; Recombinant Proteins; Splenectomy; Sulfates; Sulfur Radioisotopes; Thrombocytopenia

Using a rat bone marrow culture system, the effect of transforming growth factor beta 1 (TGF beta 1) on megakaryocyte growth and endoreduplication has been studied. Purified human platelet TGF beta 1 inhibited the number of megakaryocytes that appeared in culture at a half-maximal concentration of 0.66 +/- 0.21 ng/mL and inhibited megakaryocyte endoreduplication at a half-maximal concentration of 0.14 +/- 0.08 ng/mL. Under identical conditions, growth of erythroid precursors was half-maximally inhibited at a concentration of 0.125 ng/mL while myeloid growth was not inhibited at concentrations of TGF beta 1 up to 25 ng/mL. These profound inhibitory effects on megakaryocyte growth and endomitosis suggested that TGF beta might play a role in megakaryocytopoiesis. Therefore, we explored the effect of TGF beta in three different experimental situations by using a neutralizing antibody to TGF beta: (1) Serum but not plasma was found to inhibit the number and ploidy of megakaryocytes that grew in vitro. This inhibitory activity was completely neutralized by antibody to TGF beta or on treatment with dithiothreitol. (2) Plasma from thrombocytotic rats was observed to decrease megakaryocyte ploidy on culture but this effect was not prevented by the addition of antibody to TGF beta. (3) Plasma from thrombocytopenic but not normal rats increased megakaryocyte ploidy on culture. Addition of antibody to TGF beta did not alter these results. Therefore, TGF beta is a potent inhibitor of the number and ploidy of megakaryocytes and accounts for all the inhibition seen when megakaryocytes are cultured in serum. However, the differences in effect on megakaryocyte growth that we observe between normal, thrombocytopenic, and thrombocytotic plasmas are not due to variations in the amount of TGF beta. Furthermore, our results show that release of TGF beta from megakaryocytes during culture does not act as an autocrine regulator of megakaryocyte ploidy in vitro.

Topics: Animals; Bone Marrow Cells; Cells, Cultured; Erythropoiesis; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Megakaryocytes; Mitosis; Ploidies; Rats; Recombinant Proteins; Thrombocytopenia; Transforming Growth Factor beta

Topics: Anemia; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukins; Leukopenia; Thrombocytopenia

Hematopoietic dysfunction with peripheral cytopenias is a common complication of human immunodeficiency virus (HIV) infection. Symptomatic anemia is the most common cytopenia and occurs in the presence and absence of myelosuppressive drug therapy such as zidovudine. Drug-induced neutropenia and immune thrombocytopenia are also frequent and occur in up to 50% of acquired immunodeficiency syndrome (AIDS) patients. Attempts to reduce the impact of bone marrow failure have focused on dose reduction of zidovudine, ganciclovir, and chemotherapy, and the use of recombinant hematopoietic hormones such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Despite these maneuvers, approximately 30% of patients with AIDS receiving zidovudine will become transfusion-dependent. This has led to investigations of other cytokines that may increase blood cell formation. The recent identification of decreased number and proliferation of hematopoietic progenitors in patients with HIV infection suggests that agents which have activity on progenitor cell pools may have clinical utility. We demonstrate that human stem cell factor (HuSCF) increases burst-forming unit-erythroid (BFU-E), colony-forming unit-granulocyte-monocyte (CFU-GM), and CFU-Mix formation in vitro in normal and HIV-infected individuals. HuSCF also decreases the sensitivity of BFU-E to inhibition by zidovudine without altering HIV replication in lymphocytes or monocytes, altering peripheral blood mononuclear cell proliferation to phytohemagglutinin (PHA) and interleukin-2 (IL-2) or altering the effectiveness of zidovudine or dideoxyinosine in inhibiting HIV replication in lymphocytes or monocytes. These studies suggest that HuSCF may have clinical utility in HIV infection as an adjunctive treatment for HIV-related cytopenias.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Anemia; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Granulocytes; Hematopoietic Cell Growth Factors; HIV; HIV Infections; Humans; Lymphocytes; Macrophages; Monocytes; Neutropenia; Recombinant Proteins; Stem Cell Factor; Thrombocytopenia; Virus Replication; Zidovudine

Partially purified thrombopoietic factor (TPF) potentiated in vitro murine megakaryopoiesis induced by recombinant human erythropoietin (rh-Epo). High doses (2.5-10 units) of rh-Epo generated a considerable number of megakaryocytes in a dose-dependent manner in a serum-free liquid culture, whereas low doses of rh-Epo (0.5-1 units) failed to generate megakaryocytes. The addition of high doses of rh-Epo and TPF caused a significant increase of megakaryocytes in comparison with high doses of rh-Epo alone. Furthermore, low doses of rh-Epo with TPF caused generation of a small number of megakaryocytes, although TPF alone did not generate megakaryocytes. In addition, TPF enhanced the acetylcholinesterase (Ach-E) activity of megakaryocytes induced by rh-Epo. The potentiating effects of both factors, rh-Epo and thrombopoietic factor, may play an important role in thrombocytopenic states in vivo as well as in in vitro megakaryopoiesis.

Topics: Acetylcholinesterase; Animals; Cells, Cultured; Drug Synergism; Erythropoietin; Female; Hematopoiesis; Megakaryocytes; Mice; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

12 patients with myelodysplastic syndromes were treated with recombinant human erythropoietin (r-epo). 5 patients had stable anemia, 78-92 g/l, and 7 were transfusion-dependent. In 11 patients, r-epo was given intravenously three times a week, with dose escalation after 4 and 8 wk if hemoglobin did not increase more than 15 g/l. The doses were 600, 1500 and 3000 U/kg bodyweight/wk. The 12th patient was treated subcutaneously with a dose of 560 U/kg/wk. 3 patients showed a significant response with an increase in hemoglobin of greater than or equal to 15 g/l. 2 of these had stable anemia before treatment and increased in hemoglobin from 87 to 116 g/l and from 80 to 99 g/l, respectively. The 3rd patient was transfusion-dependent and rose to a stable hemoglobin level between 76 and 80 g/l without transfusions. 2 patients showed a reduction of their transfusion need. Mean initial serum erythropoietin in the responding group was 366 U/l compared to 1049 among the non-responders (p = 0.367). Response was observed in 5/7 patients without bone marrow sideroblasts and in 0/5 patients with sideroblasts (p = 0.027). Erythropoietin seems to be an effective and well-tolerated treatment for a certain proportion of patients with MDS. A larger patient material might provide a model for predicting responses.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Erythropoietin; Female; Fever; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Thrombocytopenia

To investigate the possible effect of preeclampsia on erythropoietin metabolism, we measured plasma and urine erythropoietin concentrations and complete blood count in 19 women with preeclampsia and nine healthy gravidas. Hemoglobin concentration and hematocrit values in the preeclamptic patients did not differ significantly from those of the normal pregnant controls. However, the plasma erythropoietin concentration tended to be higher in the preeclamptic group than in the normal pregnant controls (26.9 +/- 31.2 versus 11.2 +/- 9.9 mU/mL), though the difference was not statistically significant. Plasma erythropoietin concentration correlated negatively with both hemoglobin concentration and hematocrit (r = -0.85, P less than .01). The pattern and magnitude of the erythropoietin response to anemia paralleled that previously reported in individuals with iron deficiency anemia. No significant correlation was found between urinary erythropoietin excretion and blood pressure, qualitative albumin excretion, hematocrit, hemoglobin concentration, or plasma erythropoietin concentration. Based on our results, the erythropoietin response to anemia appears to be intact in preeclampsia, at least in the absence of renal failure.

Topics: Adult; Albuminuria; Blood Cell Count; Blood Pressure; Creatine; Erythropoietin; Female; Humans; Pre-Eclampsia; Pregnancy; Proteinuria; Thrombocytopenia; Uric Acid

We have devised a simultaneous assay system for megakaryocyte colony-stimulating factor (Meg-CSF) and megakaryocyte potentiator (Meg-Pot) by modifying a quantitative measuring technique for acetylcholinesterase activity (Ach-E) of megakaryocytes by automatic colorimetry using microplates. We cultured murine bone marrow cells treated with diisopropyl fluorophosphate in a serum-free system with serum-free pokeweek mitogen-stimulated spleen cell conditioned medium (PWM-SCM) and an unknown factor, preparing two microplates with the identical culture system. In the first plate, the total number of Ach-E-positive cells induced solely by the factor tested was indicative of Meg-CSF activity and additive increases in this parameter on simultaneous addition of PWM-SCM and the factor tested were indicative of early Meg-Pot activity. Total Ach-E activity (total change at optical density of 414 nm) per well was measured in the second plate to calculate total change at optical density of 414 nm per megakaryocyte, an indicator of late Meg-Pot activity. With this system, recombinant human erythropoietin showed both Meg-CSF and early and late Meg-Pot activities in in vitro megakaryopoiesis. Recombinant murine granulocyte-macrophage colony-stimulating factor possessed weak Meg-CSF and early Meg-Pot activity, whereas recombinant human granulocyte colony-stimulating factor exhibited late Meg-Pot activity and thrombocytopenic serum exhibited early and late Meg-Pot activities. This assay system is useful in screening Meg-CSF or Meg-Pot activities in unknown factors.

Topics: Acetylcholinesterase; Animals; Biological Factors; Bone Marrow Cells; Cells, Cultured; Colony-Stimulating Factors; Erythropoietin; Female; GPI-Linked Proteins; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Megakaryocytes; Membrane Glycoproteins; Mesothelin; Mice; Proteins; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

We studied the effects of recombinant erythropoietin (r-Epo) and thrombocytopenic serum (TS) on the cytoplasmic maturation of megakaryocytes derived from colony-forming units megakaryocyte (CFU-M). Serotonin content, ATP content, acetylcholinesterase (Ach-E) activity per megakaryocyte, and electron microscopic analysis were selected as markers of cytoplasmic maturation. Megakaryocytes induced by pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM) alone showed low levels of ATP content and Ach-E activity, which did not increase during culture, as well as a low level of serotonin content, which gradually accumulated during day 7 of culture. When r-EPo was added to the culture system on day 3 after megakaryocytic colony formation with PWM-SCM, the serotonin content in megakaryocytes increased markedly but ATP content and Ach-E activity did not increase significantly. In contrast, TS caused an increase in ATP content and Ach-E activity, but did not cause an increase in serotonin content. Electron microscopic analysis showed that the demarcation membrane system (DMS) developed defectively only in local areas with the addition of r-Epo and PWM-SCM, whereas the DMS developed normally and dense granules were generated to near normal with the addition of TS. Recombinant Epo may act on the early stage of cytoplasmic maturation, whereas TS may act on the late stage of cytoplasmic maturation. The results shown herein suggest that at least two different factors may be necessary for full in vitro cytoplasmic maturation of megakaryocytes derived from CFU-M.

Topics: Acetylcholinesterase; Adenosine Triphosphate; Animals; Cell Differentiation; Cells, Cultured; Cytoplasm; Erythropoietin; Female; Hematopoietic Stem Cells; Megakaryocytes; Mice; Rabbits; Recombinant Proteins; Serotonin; Thrombocytopenia

Erythrocytosis in a young Sinhalese man is described. The patient was known to have had a raised Hb and PCV for at least 10 years. Subsequent investigations failed to support the diagnosis of polycythaemia vera or to reveal a cause for secondary polycythaemia. Blood erythropoietin values were raised, but no cause for inappropriate secretion could be identified. Although there was no evidence of erythrocytosis in the family, the findings in this patient appear to be those of a condition which has been called familial polycythaemia. The spleen was unusually large and was associated with hypersplenism and thrombocytopenia. Problems of diagnosis and management are described. Phlebotomy appears to be the treatment of choice, with a regimen of regular venesection for the control of symptoms due to hyperviscosity and vascular occlusion.

Topics: Adult; Blood Cell Count; Blood Viscosity; Bloodletting; Diagnosis, Differential; Erythropoietin; Humans; Hypersplenism; Male; Phosphorus Radioisotopes; Polycythemia; Polycythemia Vera; Radionuclide Imaging; Thrombocytopenia

Anaemia is common in renal insufficiency and has various causes: 1) depressed marrow production of red cells, probably due to reduced production of erythropoietin, though the possibility of direct marrow inhibition on the part of uraemic toxins cannot be ruled out, together with iron deficiency, as occurs in prolonged dialysis management; 2) greater red cell destruction attributable to extraglobular factors and other mechanisms (microangiopathy, drugs, etc.); 3) greater blood loss following thrombocytopenia, reduced platelet adhesivity and agglutinability, dialysis. The main premisses on which the treatment of anaemia of uraemic patients is based are discussed.

Topics: Anemia; Bone Marrow Cells; Cell Survival; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis; Thrombocytopenia

The effects of administration of partially purified human urinary erythropoietin and rabbit thrombopoietin, and of endogenously produced erythropoietin and thrombopoietin on both red cell and platelet production were examined in mice. Partially purified thrombopoietin was prepared from rabbit plasma by sequential fractionation with ammonium sulfate precipitation, and DEAE and Sephadex G-100 chromatography. Preparations of thrombopoietin and partially purified human urinary erythropoietin (NIH No. H-11-TaLSL) were administered subcutaneously to normal mice, and the rate of incorporation of selenomethionine-75 Se into platelets was measured as an index of thrombopoietic activity of the infused material. Erythropoietin and thrombopoietin were assayed for erythropoietic activity by measuring the rate of appearance of 59Fe in the red cells of posthypoxic polycythemic mice. Preparations containing thrombopoietin had barely measurable erythropoietic activity, and 7 units of partially purified erythropoietin had little thrombopoietic activity. When endogenous levels of erythropoietin were increased by hypoxia, platelet production was not enhanced. Similarly, increased levels of thrombopoietin, induced in response to thrombocytopenia produced by platelet antiserum, did not alter red cell production. These data suggest that physiologically increased levels of thrombopoietin do not stimulate erythropoiesis, and that physiologically increased levels of erythropoietn do not stimulate thrombopoiesis. However, currently available, partially purified preparations of erythropoietin and thrombopoietin may be capable of stimulating both platelet and red cell production if used in sufficient quantities.

Topics: Animals; Blood Platelets; Cell Differentiation; Erythrocytes; Erythropoiesis; Erythropoietin; Glycoproteins; Humans; Hypoxia; Iron Radioisotopes; Mice; Polycythemia; Rabbits; Selenomethionine; Thrombocytopenia; Thrombopoietin

The effects of hemorrhage, hypoxia, or a preparation of erythropoietin on platelet production were investigated by measuring incorporation of selenomethionine-75Se (75SeM) into the platelets of rabbits or mice. Rabbits that were bled daily for 5 days had a significant increase in the platelet count, 48 hours after cessation of hemmorrhage, that coincided with a threefold increase in isotope incorporation into platelets. Mice that were bled daily for 3 days also had significantly higher platelet counts and a 38 per cent increase in incorporation of isotope into platelets, 3 days after the last hemorrhage. Normal rabbits, injected with plasma from repeatedly bled, anemic, and moderately thrombocytopenic rabbits, had a 58 per cent greater maximum incorporation of 75SeM than did control animals. Mice exposed to hypoxia for 6 days had a mean platelet count 23 per cent lower than normal controls, but no change in incorporation of 75SeM into platelets. Plasma from hypoxic mice did not stimulate platelet production when injected into normal mice. A preparation of human urinary erythropoietin (15 to 30 U. per mouse or 30 to 120 U. per rabbit) significantly increased incorporation of isotope into the platelets of normal mice and rabbits. The results demonstrated that hemorrhage, but not hypoxia, is associated with increased thrombopoietic activity in plasma. However, large doses of preparations of human erythropoietin contained detectable thrombopoietic activity.

Topics: Animals; Blood Platelets; Erythropoietin; Hematopoiesis; Hemorrhage; Hypoxia; Mice; Plasma; Rabbits; Selenomethionine; Thrombocytopenia

In mice hypoxic hypoxia (0.5 atm.) results in a severe and persistent thrombocytopenia with a rapid decline in the platelet count between the fifth and ninth days of hypoxia, after which platelet counts level off at about half their normal value. The thrombocytopenia is not due to the associated polycythemia, splenomegaly, or increased blood volume. There is no significant change in platelet counts of mice made polycythemic by daily injections of 6 units of erythropoietin. Fifteen days of hyperbaria (3 atm.) has no effect on the platelet count of otherwise normal mice. Since there is only a slight decline in platelet count during the first 5 days of hypoxia, the persistent thrombocytopenia appears to be due to either a decreased rate of production of platelets or a structural or metabolic defect in platelets produced under conditions of hypoxia.

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Transfusion; Blood Volume; Body Weight; Erythropoietin; Female; Hematocrit; Hyperbaric Oxygenation; Hypoxia; Mice; Mice, Inbred C3H; Organ Size; Polycythemia; Spleen; Splenectomy; Thrombocytopenia

Topics: Autoradiography; Blood; Bone Marrow; Bone Marrow Cells; Cell Division; Cells, Cultured; Culture Media; Erythropoiesis; Erythropoietin; Humans; Infant; Infant, Newborn; Thrombocytopenia; Thymidine; Tritium; Umbilical Cord

Topics: Animals; Blood Platelets; Blood Transfusion; Coenzyme A; Erythropoietin; Glutathione; Pantothenic Acid; Rabbits; Rats; Thrombocytopenia; Thrombocytosis; Thrombopoietin; Vitamins

Topics: Anemia; Anemia, Hypochromic; Anemia, Iron-Deficiency; Anemia, Macrocytic; Blood Platelets; Bone Marrow Cells; Drug Therapy; Epoetin Alfa; Erythropoietin; FIGLU Test; Folic Acid; Folic Acid Deficiency; Glutamates; Hemoglobins; Humans; Infant; Infusions, Parenteral; Injections, Intravenous; Iron; Iron-Dextran Complex; Megakaryocytes; Reticulocytes; Thrombocytopenia; Thrombocytosis; Vitamin B 12